This project is focused on understanding the mechanism of how cells irreversibly exit the cell cycle and go senescent. While low doses of stress can send cells into quiescence, a transient cell cycle arrest, large doses of stress or prolonged exposure to stress can cause cells to permanently exit the cell cycle in a process called senescence. Cellular senescence plays a beneficial role in preventing tumorigenesis but the steady accumulation of senescent cells over the life of an organism is thought to underlie the adverse consequences of aging. Senescence is thought to require the activation of either p53 or Rb and is regulated in part by the cell-cycle inhibitor p16, which is a CKI that inhibits CDK4/6. Despite the importance of senescence in health and disease, little is known about the signaling dynamics that govern entry into senescence and the signaling processes that maintain senescence irreversibly, largely due to a reliance on bulk-cell assays as well as long-interval timepoints usually on the order of days. Interestingly, several reports have implicated premature re-activation of the APC/C during G2 phase in response to large doses of DNA damage in inducing senescence. However, the mechanism underlying APC/C re-activation and its role in senescence is poorly understood. We are currently investigating the molecular mechanism underlying APC/C reactivation in response to DNA damage as well as the consequences for failing to re-activate the APC/C.